Therapeutic Potential of Exosomal miRNAs from Mesenchymal Stem Cells for Neurodegenerative Diseases: A Systematic Review

Abstract

Background Exosomes are nanoscale extracellular vesicles capable of crossing the blood–brain barrier and delivering functional microRNAs (miRNAs), positioning them as promising vectors for cell-free therapies in neurodegenerative diseases. Mesenchymal stem cell (MSC)-derived exosomal miRNAs have emerged as key regulators of interconnected pathogenic pathways, including neuroinflammation, oxidative stress, apoptosis, and protein aggregation. Objectives This systematic review aimed to critically evaluate the therapeutic potential and mechanistic roles of MSC-derived exosomal miRNAs in neurodegeneration. Methods A comprehensive search over 12 years (2014–2026) across PubMed, Scopus, Web of Science, and ScienceDirect identified 157 studies, of which 10 met the inclusion criteria. Results Across the included experimental models, exosomal miRNAs, including miR-23b-3p, miR-23a-3p, members of the miR-29 family, miR-214-3p, and miR-223, consistently promoted neuroprotection and functional recovery. These effects were associated with modulation of key molecular pathways, including Wnt/β-catenin signaling, PI3K/Akt activation, and BACE1-mediated amyloid processing. Although methodological variability was observed among studies, particularly regarding exosome characterization and validation of miRNA cargo, the reported findings consistently demonstrated therapeutic benefits.Across experimental models, exosomal miRNAs such as miR-23b-3p, miR-23a-3p, members of the miR-29 family, miR-214-3p, and miR-223 consistently promoted neuroprotection and functional recovery by modulating key pathways, including Wnt/β-catenin signaling, PI3K/Akt activation, and BACE1-mediated amyloid processing. However, despite these promising findings, some methodological variability was observed across studies, particularly regarding exosome characterization and validation of miRNA cargo, which may influence reproducibility. Nevertheless, the overall body of evidence consistently supports the therapeutic potential of MSC-derived exosomal miRNAs in neurodegenerative disorders. Conclusions This systematic review demonstrates that MSC-derived exosomal miRNAs act as key regulators of interconnected pathways involved in neurodegeneration, including neuroinflammation, apoptosis, oxidative stress, and protein aggregation. Notably, miR-23b-3p, miR-29 family members, miR-22, miR-34b, and miR-214-3p emerged as consistent neuroprotective candidates across different models.These findings support the concept that MSC-derived extracellular vesicles function as multi-target delivery systems capable of modulating disease-relevant pathways at a systems level.

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